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‘United grates Patent
" ce
1
3,068,249
Patented Dec. 11, less
2
spirit or in scope.
3,063,249
In these examples, temperatures are
given in degrees centigrade (° 0.), and quantities of
materials in parts by weight unless otherwise noted.
ALKYL ETHERS U1? Uni?‘YDROCAREGN-SUEESTL
TUTEEESTR-éhhliié,17-)3911318
Example 1
Frank B. (Zolton, éChicago, and Richard E. Bay, Morton
Grove, lib, assignors to G. D. Searie 8r ?x, Chicago,
1132., a. corporation of Delaware
No Brewing. Filed 11cc. 15, 1960, Ser. No. 75,915
4 Qlaims. (Cl, 260-3975)
A mixture of 14 parts of 17a-ethynylestr-4-ene-3?,17,8
diol, 0.5 part of p-toluenesulfonic acid, and 200 parts of
methyl alcohol is stored at room temperature for about
v24 hours, then poured into ice water. The resulting
The present invention is concerned With novel steroidal 10 aqueous mixture is extracted with ethyl acetate, and the
organic layer is washed with Water, then dried over an
alkyl ethers and, more particularly, With alkyl ethers of
hydrous sodium sulfate. Removal of the solvents by
l71(hydrocarbon-substituted)estr-4-ene-3,17-diols as rep
concentration in vacuo affords a semicrystalline residue,
resented by the structural formula
which is dissolved in benzene and chromatographed on
15 silica gel.
The chromatographic column is eluted with
benzene solutions containing increasing proportions of
ethyl acetate. The 5% ethyl acetate in benzene eluate
is concentrated to dryness, and the resulting residue is
" crystallized from acetone-hexane to yield l7a-ethynyl-3?
20 methoxyestr-4-en-17?-ol, M.P. about 159—172°. Recrys
tallization from acetone-hexane a?ords a pure sample
melting at about 172-179°. It displays infrared absorp
n
wherein R is a lower alkyl radical, R’ is hydrogen or a
lower alkyl radical, and X is a hydrocarbon substituent 25
selected from the class comprising lower alkyl, alkenyl,
and alkynyl radicals.
Examples of the aforementioned lower hydrocarbon
radicals are methyl, ethyl, propyl, butyl, pentylfhexyl,
vinyl, propenyl, hexenyl, ethynyl, propynyl, pentynyl,
hexynyl, and the branched-chain isomers thereof.
The compounds of this invention are conveniently
manufactured by alkylation of the corresponding 17-sub
stituted estr-4-ene-3,l7-diols. Treatment of the appro
priate diol with methanol in the presence of an acidic
catalyst produces the instant 3-monomethyl others. A
speci?c example of this process is the reaction of 17cc
ethynylestr-4~ene-3e,17,8-diol with methanol and p-tolu
enesulfonic acid to afford l7a-ethynyl-3p-methoxy~estr-4~ 40
en-l7/3~ol.
The instant 3,17-diethers are obtained by alkylation
of the disodium derivative of the aforementioned diols
tion maxima at about 2.72, 3.00, and 9.15 microns.
Example 2
A mixture of 3 parts of 17a-(l-propyny1)estr-4-ene
33,17,8-diol, 0.1 part of p-toluenesulfonic acid, and 60
parts of methyl alcohol is stirred at room temperature
for about 41/2 hours, then poured into ice water. The
resulting crystals are collected by ?ltration, washed with
water, and dried to yield crude 3B-methoxy-17a-(1
propynyDestr-4-en-1750i, MP. about 53-70". This
crude product is dissolved in benzene and chromato
graphed on silica gel. Elution with 5% ethyl acetate in
benzene a?ords a fraction, which is crystallized from
acetone-hexane to produce pure 3/3-m-ethoxy-17a-(L
propynyl)estr-4-en-l7,8-ol, M.P. about 122—l26°. This
substance is characterized by infrared absorption maxima
at about 2.75, 6.00, and 9.18 microns.
Example 3
To 140 parts of liquid ammonia is added with stirring
?rst 0.01 part of ferric nitrate, then 2.3 parts of sodium
portionwise over a period of about 15 minutes. Stirring
with the appropriate alkyl halide. For example, 1701.
ethynylestr-4-ene-3,8,l7?-diol is treated with sodium in 45 is continued for about 15 minutes, and a solution of 10
parts of 17et-ethynylestr-4-ene-3;3,17,8-diol in 133 parts of
liquid ammonia to form the disodium derivative, then with
tetrahydrofuran is added dropwise over a period of about
methyl iodide to produce l7m-ethynylestr-4-ene~3B,17B
15 minutes. This mixture is stirred for about 2 hours,
diol 3,17-dimethyl ether.
and a solution of 9.58 parts of methyl iodide in 35 parts
The 17a-alkenyl compounds of this invention can be
produced by the methods described supra or, alterna 50 of ether is then added dropwise. Stirring is continued
tively, by partial catalytic hydrogenation of the corre
sponding l7a-alkynyl compound. A typical embodiment
for about one hour, and the ammonia is allowed to evap
orate from the stirred mixture over a period of about 15
hours. The residual mixture is poured into water, acidi
of this process involves the reduction of 17u-ethynyl-35
?ed with acetic acid, then extracted with ethyl acetate.
methoxyestr-4-en-l7?-ol with hydrogen in the presence
This
organic solution is washed successively with aqueous
of a 5% palladium—on-calcium carbonate catalyst to af 55
sodium bicarbonate and water, dried over anhydrous so
ford 3B-methoxy-17a-vinylestr-4-en-17,8-01.
The compounds of this invention are useful as a re
sult of their valuable pharmacological properties. In
dium sulfate, and concentrated to dryness in vacuo. The
oily residue is dissolved in benzene and chromatographed
on alumina. Elution with 2% ethyl acetate in benzene
particular, they are able to induce the uterine endometrial
proliferation typical of progesterone, in contrast to the 60 altords pure 17a-ethynylestr-4-ene-3B,17/3-di0l 3,17 - di
rnethyl ether ‘as a clear oil. Infrared maxima are ob
estrogenic e?ect produced by related prior art composi
served at about 3.01 and 9.16 microns.
tions.
Example 4
The following examples illustrate the invention more
fully, but are not to be construed as limiting, either in
To a solution of 8.4 parts of 17ot-ethylestr-4-ene-3p,
3,068,249
4
L9‘
17,8-diol in 200 parts of methanol is added 0.75 part of
Example 8
p-toluenesulfonic acid monohydrate, and the resulting
The substitution of an equivalent quantity of 1701-(1
propynyl)estr-4-ene-3?,l7?-diol in the procedure of Ex—
5 hours, then neutralized with sodium acetate and diluted
ample 3 results in 17<x-(l-propynyl)estr-4-ene-3[i,17[3-diol
with water. Extraction with ether a?ords an organic 5
3,17-din1ethyl ether.
solution which is Washed with water, dried over anhydrous
What is claimed is:
sodium sulfate, and concentrated in vacuo. A solution
1. A compound of the structural formula
of the oily residue in benzene is chromatographed on
silica gel. Elution with ‘10% ethyl acetate in benzene
produces a fraction, which is crystallizes from ether-pen
mixture is allowed to stand at room temperature for about
tane to yield 17ot-ethyl-3,8-methoxyestr-4-en-1753-01, M.P.
109—110°; [a]D=+l55° (chloroform). Infrared max
ima are observed at about 2.71, 5.99, and 9.12 microns.
Example 5
To a solution of 2.23 parts of 17¢x-ethynyl~35-meth
oxyestr-4-en-176-ol in 150 parts of pyridine is added one
part of 5% palladium-on-calcum carbonate catalyst and
this
one
gen
and
mixture is stirred under hydrogen at a pressure of
atmosphere until one molecular equivalent of hydro
is adsorbed. The catalyst is removed by ?ltration,
the ?ltrate is diluted with water, then extracted with
wherein X is a lower alkynyl radical.
2. l7ot-ethyl-3B-methoxyestr-ll-en-175-01.
3. 17a-ethynylestr-4-ene-3B,l7?-diol 3,17 - dimethyl
ether.
4. A compound of the structural formula
ether. The organic layer is washed successively with
dilute hydrochloric acid, aqueous sodium bicarbonate,
water, and saturated aqueous sodium chloride, then dried
over anhydrous sodium sulfate, and ?nally concentrated
in vacuo to produce an oily residue. This residue is
recrystallized twice from aqueous acetone to afford 3d
OH
CH
rnethoxy-17e-vinylestr-4-en-175-01, M.P. about 50—60‘°.
Example 6
The substitution of an equivalent quantity of 3?-rneth
oxy-17a-(l-propynyl)estr-4-en-l7c-ol in the procedure of
Example 5 results in 3,3-methoxy-l7a-propenylestr-4-en
175-01.
Example 7
SE30
30 wherein X is a lower alkyl radical.
By substituting an equivalent quantity of l7a-meth
ylestr-4-ene-3;8,17/3-diol and otherwise proceeding accord
ing to the process of Example 4, 3B~methoxy-17a-methyl
40
estr-4-en-17?-ol is obtained.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,843,609
Colton _______________ __ July 15, 1958